Antineoplastic modified imidazoacridines

ABSTRACT

Compounds of formula I &lt;CHEM&gt;  in which: R represents: -OH or -OR min , wherein R min  represents C1-C6 alkyl, R1&lt;a&gt; and R1&lt;b&gt;, which may be identical or different, represent hydrogen or C1-C6 alkyl, unsubstituted or substituted by a hydroxyl, an amino, a N min -alkylamino or a N min ,N min -dialkylamino group, such N min -alkyl groups containing 1-4 carbon atoms,     n is 2-5 and     R2 represents hydrogen, or straight chain C1-4 alkyl, in the form of a free base or a pharmaceutically acceptable acid addition salt or an N-oxide are useful in antineoplastic treatment and prophylaxis, especially of leukaemias.

This invention relates to antineoplastic compounds of particularinterest for the treatment of leukemia, to the use thereof, processesfor the production of such compounds and intermediates therefor.

Accordingly, the present invention comprises a compound of formula I,optionally in the form of an acid addition salt: ##STR2## in which

R represents: --OH or --OR' (wherein R' represents alkyl, e.g. C₁ -C₆alkyl such as methyl).

R₁ ^(a), and R₁ ^(b), which may be identical or different, representhydrogen or alkyl (e.g. C₁ -C₃ alkyl such as methyl) which is optionallysubstituted e.g. by a hydroxyl, an amino, a N-alkyl-amino or aN,N'-dialkylamino group as, for example in the substituents:hydroxyethyl, aminoethyl, N-alkylaminoethyl and N,N'-dialkylaminoethyl,such N-alkyl groups preferably containing 1-4 carbon atoms.

n is 2-5 and

R₂ represents hydrogen, or alkyl.

The group R is usually located at the 8-position. R₁ ^(a) and R₁ ^(b)are normally identical and represent alkyl groups e.g. C₁ -C₆ alkylgroups such as methyl or ethyl, n typically being 2 or 3.

R₂ generally represents hydrogen, straight chain C₁ -C₄ alkyl e.g.methyl or branched chain C₃ -C₆ alkyl.

Addition salts, which are generally pharmaceutically acceptable, may beof both organic and inorganic acids. Examples of suitable acids for saltformation are: hydrochloric, sulfuric, phosphoric, acetic, citric,malonic, ascorbic, maleic, methanesulfonic, lactic, gluconic,glucoronic, and the like. Usually the compound I is present in the formof a hydrochloride and may be hydrated.

The following compounds of formula I are of particular interest:

A. R=9--OH; R₁ ^(a) =R₁ ^(b) =--CH₃ ; R₂ =H; n=2.

B. R=8--OH; R₁ ^(a) =R₁ ^(b) =--CH₃ ; R₂ =CH₃ ; n=2.

C. R=8--OCH₃ ; R₁ ^(a) =R₁ ^(b) =--CH₃ ; R₂ =H; n=2.

D. R=8--OH; R₁ ^(a) =R₁ ^(b) =--CH₂ CH₃ ; R₂ =H; n=2.

E. R=8--OH; R₁ ^(a) =R₁ ^(b) =--CH₂ CH₃ ; R₂ =CH₃ ; n=2.

F. R=8--OCH₃ ; R₁ ^(a) =R₁ ^(b) =--CH₂ CH₃ ; R₂ =H; n=2.

G. R=8--OH; R₁ ^(a) =R₁ ^(b) =--CH₃ ; R₂ =CH₃ ; n=3.

H. R=8--OH; R₁ ^(a) =R₁ ^(b) =--CH₂ CH₃ ; R₂ =H; n=3.

Compounds A, B, E, F and H are of especial interest.

Compounds of formula I in which R₂ represents hydrogen or C₁ -C₆ alkylmay be produced by treating a compound of formula II optionally in theform of an acid addition salt thereof, ##STR3## respectively with formicacid or a compound of formula R₂ CON(CH₃)₂.

Treatment is generally conducted at elevated temperature, typically atreflux.

Compounds of formula II optionally in the form of acid addition saltsmay be produced from compounds of formula III by treatment thereof toreduce the nitro group to the corresponding amino group: ##STR4##

Such treatment may be carried out by means of a reducing agent such ashydrazine hydrate suitably in the presence of a catalyst e.g. RaneyNickel in a polar solvent such as tetrahydrofuran (THF). Theintermediates II obtained are generally extremely unstable to oxygen,especially in those compounds wherein n represents 3 and are usuallyused as starting materials for conversion to compounds of formula I inthe form of acid addition salts, for example hydrochlorides.

The present invention further includes within its scope an intermediateof formula II, preferably in the form of an acid addition salt.

Two methods are generally used for isolation of the final products. Inthe case of methoxy derivatives, the products may be extracted withbenzene or chloroform from the reaction mixture after rendering themixture alkaline and next transformed into dihydrochlorides. The hydroxycompounds may instead be isolated as hydrochloride salts directly fromthe reaction mixture after acidification with HCl.

Compounds of formula I are of interest for the treatment or prophylaxisof cancers and in particular as antineoplastic agents in the treatmentof leukemia.

Accordingly, in a further aspect the present invention comprises acompound of formula I for use in therapy and, in a yet further aspect ofthe present invention, comprises the use of a compound of formula I forthe manufacture of a medicament useful in the treatment or prophylaxisof a cancer and in particular of leukemia.

The dosage form and amount can be readily established by reference toknown treatment or prophylactic regimens. In general, however, thedosage of the compound of formula I usually lies within the range about0.1 mg to about 50 mg/kg, preferably 0.5 mg to 10 mg/kg.

While it is possible for the active compound of formula I orpharmaceutically acceptable salt thereof to be administered alone, it ispreferable to present the active compound as a pharmaceuticalformulation. Formulations of the present invention for medical usecomprise the active compound together with one or more pharmaceuticallyacceptable carriers therefor, and optionally, any other ingredientswhich may be therapeutic per se, synergistic with the compound offormula I, or both. Carrier(s) are generally, of course,pharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

In accordance with a further aspect, the present invention comprises apharmaceutical formulation comprising a compound of formula (I) (in theform of the free base or a pharmaceutically acceptable acid additionsalt) together with a pharmaceutically acceptable carrier therefor.

Formulations suitable for oral, rectal, topical or parenteral (includingsubcutaneous, intramuscular and intravenous) administration areincluded.

Formulations may be conveniently presented in unit dosage form and maybe prepared by a methods well known in the art of pharmacy. All methodsgenerally include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. Usually, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier or with a finely divided solid carrier or with both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension in an aqueous liquid ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.The active compound may also be presented as a bolus, electuary orpaste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, the active compound in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Tablets may be made by moulding a mixture of the powdered activecompound with any suitable carrier in a suitable machine.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may be addedan accessory ingredient. Such accessory ingredient(s) may includeflavourings, an agent to retard crystallisation of the sugar or an agentto increase the solubility of any other ingredient, such as a polyhydricalcohol, for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a usual carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient.

In addition to the aforementioned ingredients, formulations of thisinvention, for example ointments, creams and the like, may include oneor more accessory ingredient(s) selected from diluents, buffers,flavouring agents, binders, surface active agents, thickeners,lubricants, preservatives (including antioxidants) and the like.

The present invention is illustrated by the following Examples:

EXAMPLES General Procedure

Compounds of formula I, the subject of Examples 1 to 16, are produced bythe route outlined in Scheme 1. ##STR5##

In the following Examples melting points are taken on a Bushi 510capillary melting points apparatus and are uncorrected ¹ H NMR spectrawere recorded on a Varian VXR-300 spectrometer operating at 300 MHz.Chemical shifts are reported as δ units in ppm downfield from internaltetramethylsilane. NMR abbreviations used are as follows: br(broad),s(singlet), d(doublet), t(triplet), qu(quartet), qt(quintet),m(multiplet), ex(exchangeable with deuterium oxide). Quartets which byaddition of deuterium oxide are transformed into triplets are labeledwith *. Single frequency decoupling was utilized to assign specificprotons. Coupling constants are given in Hz. Microanalytical results,indicated by atomic symbols, are within ±0.4% of the theoretical valuesand are obtained from Laboratory of Elemental Analyses, Department ofChemical Sciences, University of Camerino.

EXAMPLE 1 A.1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-4-nitro-9(1OH)-cridinone

A mixture of 4.57 g (0.015 mol)1-chloro-7-methoxy-4-nitro-9(1OH)-acridinone, 25 ml DMF and 7.00 g (0.06mol) 2-diethylaminoethylamine is stirred and heated at 60° C. for 30minutes. 100 ml 40% (v/v) MeOH-water solution is added to the reactionmixture, heated to boiling and after cooling left overnight in arefrigerator. The crystallized product is collected by filtration washedwith water (150 ml) and MeOH (50 ml) and dried to give 5.30 g. (92%)analytically pure product as yellow needles: mp 178°-179° C. (lit. mp.Capps. D. B. European Patent Appl. E.P. 145226, 1985; Chem. Abstr. 1985,103, 215182s. 179°-180° C.);

B. Preparation of 7-Substituted4-amino-1-[[(dialkylamino)alkyl]amino]-4-nitro-9(1OH)-acridinoneHydrochloride Salts

To a mixture of nitro derivatives (0.01 mol), 200 ml THF, and about 2.5g of Raney Ni is added with stirring at room temperature then 2 mlhydrazine monohydrate, and stirring if continued for about 30 minutes.The catalyst is filtered off and washed with THF (50 ml). The filtrateis quickly treated with 10 ml concentrated hydrochloric acid and stirredfor 10 minutes. The yellow precipitate obtained is collected and washedwith THF. The product is recrystallized from a solution of MeOH(90%)-dioxane made acidic with HCl (pH˜2).

C. Preparation of5-[[2-(Diethylamino)ethyl]amino]-8-methoxyimidazo[4,5,1-de]acridin-6-one Dihydrochloride

A mixture of 1.71 g (4 mmol) of the product from the procedure ofExample 1B and 20 ml (95% formic acid is heated at reflux for 6 h. Acidis evaporated and the residue is dissolved in water (100 ml). Thesolution is made basic (pH 9) by addition of sodium carbonate andproduct is extracted with chloroform (2×100 ml). The organic extractsare dried and evaporated to give a residue which is dissolved in EtOH.The solution is made acidic with HCl and product is crystallized byaddition of acetone to give the title product.

EXAMPLE 2

Compound I: n=2, R=OCH₃, R₁ =CH₃, R₂ =H.

The procedures 1A, 1B and 1C of Example 1 are followed butdimethylaminoethylamine is used in place of diethylaminoethylamine in1A.

EXAMPLE 3

Compound I: n=2, R=OCH₃, R₁ =CH₃, R₂ =CH₃.

The procedures 1A and 1B of Example 1 are followed usingdimethylaminoethylamine in place of diethylaminoethylamine. The productis then subjected to the following procedure (designated 3C):

A mixture of 2.14 g (5 mmol) hydrochloride and 30 ml DMA is refluxed for12 h, 200 ml water is added to the reaction mixture, made basic withsodium hydroxide and the product is extracted with benzene (2.150 ml).The extracts are evaporated to dryness and the residue is dissolved inmethanol-dioxane (1:1) mixture. The solution is made acidic with gaseousHCl and the crystallized product is collected by filtration to giveyellow crystals.

EXAMPLE 4

Compound I: n=2, R=OCH₃, R₁ =CH₂ CH₃, R₂ =CH₃.

The procedures 1A and 1B of Example 1 are followed and the product issubjected to procedure 3C.

EXAMPLE 5

Compound I: n=3, R=OCH₃, R₁ =CH₃, R₂ =H.

The procedures 1A, 1B and 1C of Example 1 are followed butdimethylaminopropylamine is used in place of diethylaminoethylamine inprocedure 1A.

EXAMPLE 6

Compound I: n=3, R=OCH₃, R₁ =CH₃, R₂ =CH₃.

The procedure of Example 5 is followed but procedure 3C replacedprocedure 1C.

EXAMPLE 7

Compound I: n=3, R=OCH₃, R₁ =CH₂ CH₃, R₂ =H.

The procedures 1A, 1B and 1C of Example 1 are followed butdiethylaminopropylamine is used in place of diethylaminoethylamine inprocedure 1A.

EXAMPLE 8

Compound I: n=3, R=OCH₃, R₁ =CH₂ CH₃, R₂ =CH₃.

The procedure of Example 7 is followed but procedure 3C replacesprocedure 1C.

EXAMPLE 9

Compound I: n=2, R=OH, R₁ =CH₃, R₂ =H.

The procedure of Example 1 is followed but dimethylaminoethylamine isused in place of diethylaminoethylamine and1-chloro-7-hydroxy-4-nitro-9(1OH)-acridone is used in place of1-chloro-7-methoxy-4-nitro-9-(1OH)-acridone in procedure 1A andprocedure 1C is replaced by the following, designated 9C:

A mixture of 5 mmol of dihydrochloride salt and 20 ml of 95% formic acidis refluxed for 8 h. Formic acid is evaporated and the residue isdissolved on heating in methanol. 3 ml conc. hydrochloric acid is addedto the hot solution and the product is crystallized by addition ofacetone. The product is collected by filtration and recrystallized froma methanol-acetone mixture.

EXAMPLE 10

Compound I: n=2, R=OH, R₁ =CH₃, R₂ =CH₃.

The procedure of Example 9 is followed but the following procedure,designated 10C, replaces 9C:

A mixture of 5 mmol of dihydrochloride salt and 25 ml of DMA is refluxedfor 12 h. About 20 ml of the solvent is evaporated, 100 ml acetone isadded to the residue and acidified with gaseous HCl. The precipitatedproduct is collected by filtration and washed with acetone. Crudeproduct is recrystallized (if necessary twice) from methanol-acetone togive the respective dihydrochloride salt.

EXAMPLE 11

Compound I: n=2, R=OH, R₁ =CH₂ CH₃, R₂ =H.

The procedure of Example 9 is followed but diethylaminoethylamine isused in place of dimethylaminoethylamine in procedure 1A.

EXAMPLE 12

Compound I: n=2, R=OH, R₁ =CH₂ CH₃, R₂ =CH₃.

The procedure of Example 10 is followed but diethylaminoethylamine isused in place of dimethylaminoethylamine in procedure 1A.

EXAMPLE 13

Compound I: n=3, R=OH, R₁ =CH₃, R₂ =H.

The procedure of Example 9 is followed but dimethylaminopropylamine isused in place of dimethylaminoethylamine in procedure 1A.

EXAMPLE 14

Compound I: n=3, R=OH, R₁ =CH₃, R₂ =CH₃.

The procedure of Example 13 is followed but procedure 10C replacesprocedure 9C.

EXAMPLE 15

Compound I: n=3, R=OH, R₁ =CH₂ CH₃, R₂ =H.

The procedure of Example 13 is followed but diethylaminopropylamine isused in place of dimethylaminopropylamine in procedure 1A.

EXAMPLE 16

Compound I: n=3, R=OH, R₁ =CH₂ CH₃, R₂ =CH₃.

The procedure of Example 15 is followed but procedure 10C replacesprocedure 9C.

NMR data for intermediates and final products follows with reference toScheme 1:

Compound (b): R=OCH₃, R₁ =CH₂ CH₃, n=2.

¹ H NMR (Me₂ CO-d₆) δ 12.48(s,1H,ex,N10-H), 11.90(t,1H,ex,--NH--CH₂ --),8.34(d,1H,J=9.8,C3-H), 7.93(d,1H,J=9.0,C5-H), 7.56(d,1H,J=3.0,C8-H),7.40(dd,1H,J=8.9,J=3.0,C6-H), 6.54(d,1H,J=9.8,C2-H), 3.87(s,3H,--OCH₃),3.49(qu*,2H,--NH--CH₂ --CH₂ --), 2.73(t,2H,--CH₂ --CH₂ --NEt₂),2.58(qu,4H,--N(CH₂ CH₃)₂), 1.02(t,6H,--N(CH₂ --CH₃ (₂).

Compound (b): R=OH, R₁ =CH₂ CH₃, n=2.

¹ H NMR (Me₂ SO-d₆) δ 12.40(s,1H,ex, N10-H), 11.92(t,1H,ex,--NH--CH₂--), 9.74(s,1H,ex,--OH), 8.34(d,1H,J=9.8,C3-H), 7.79(d,1H,J=8.9,C5-H),7.55(d,1H,J=2.8,C8-H), 7.26(dd,1H,J=8.9,J=2.8,C6-H),6.53(d,1H,J=10.0,C2-H), 3.49(qu*,2H,--NH--CH₂,--CH₂ --), 2.74(t,2H,--CH₂--CH₂ --NEt₂), 2.58(qu,4H,--N(CH₂ --CH₃)₂), 1.02(t,6H,--N(CH₂ --CH₃)₂).

Compound (c): R=OCH₃, R₁ =CH₂ CH₃, n=3.

¹ H NMR (Me₂ SO-d₆ +D₂ O) δ 7.80(d,1H,J=9.0,C5-H),7.58(d,1H,J=3.0,C8-H), 7.55(d,1H,J=8.8, C3-H),7.43(dd,1H,J=9.0,J=3.0,-C6-H), 6.35(d,1H,J=8.8,C2-H), 3.85(s,3H,--OCH₃),3.35(t,2H,--NH--CH₂ --CH₂ --), 3.12(m,6H,--CH₂ --N(CH₂ --CH₃)₂),2.07(m,2H,--CH₂ --CH₂ --CH₂ --), 1.23(t,6H,--N(CH₂ CH₃)₂).

Compound I: R=OCH₃, R₁ =CH₂ CH₃, R₂ =H, n=2.

¹ H NMR (free base)(Me₂ SO-d₆) δ 9.13(s,1H,C1-H), 8.98(t,1H,ex,--NH--CH₂--), 8.36(d,1H,J=9.1,C10-H), 7.98(d,1H,J=8.9,C3-H),7.79(d,1H,J=3.0,C7-H), 7.52(dd,1H,J=9.1,J=3.0,C9-H),6.80(d,1H,J=8.9,C4-H), 3.92(s,3H,--OCH₃), 3.42(qu*,2H,--NH--CH₂ --CH₂--), 2.73(t,2H,--CH₂ --CH₂ --NEt₂), 2.58(qu,4H,--N(CH₂ --CH₃)₂),1.02(t,6H,--N(CH₂ --CH₃)₂).

Compound I: R=OCH₃, R₁ =CH₂ CH₃, R₂ =CH₃, n=2.

¹ H, NMR (free base) (Me₂ SO-d₆) δ 8.98(t,1H,ex,--NH--CH₂),8.12(d,1H,J=9.2,C10-H), 7.82(d,1H,J=3.2,C7-H), 7.80(d,1H,J=8.8,C3-H),7.43(dd,1H,J=9.2,J=3.2,C9-H), 6.70(d,1H,J=8.8,C4-H), 3.91(s,3H,--OCH₃),3.38(qu*,2H,--NH--CH₂ --CH₂ --), 3.00(s,3H,Cl--CH₃), 2.72(t,2H,--CH₂--CH₂ --NEt₂), 2.58(qu,4H,--N(CH₂ --CH₃)₂), 1.03(t,6H,--N(CH₂ --CH₃)₂).

Compound I: R=OH, R₁ =CH₂ CH₃, R₂ =H, n=2.

¹ H NMR (free base) (Me₂ SO-d₆) δ 10.00(s,1H,ex,C8-OH), 9.08(s,1H,C1-H),8.99(t,1H,ex,--NH--CH₂ --), 8.26(d,1H,J=8.9,C10-H),7.95(d,1H,J=8.8,C3-H), 7.72(d,1H,J=2.8,C7-H),7.33(dd,1H,J=8.9,J=2.8,C9-H), 6.77(d,1H,J=8.8,C4-H),3.40(qu*,2H,--NH--CH₂ --CH₂ --), 2.70(t,2H,--CH₂ --CH₂ --NEt₂),2.56(qu,4H,--N(CH₂ --CH₃)₂), 1.01(t,6H,--N(CH₂ --CH₃)₂).

Compounds I: R=OH, R₁ =CH₂ CH₃, R₂ =H, n=3.

¹ H NMR (free base) (ME₂ SO-d₆) δ 10.02(brs,1H,ex,C8-OH),9.10(s,1H,C1-H), 8.93(t,1H,ex,--NH--CH₂ --), 8.27(d,1H,J=8.9,C10-H),7.97(d,1H,J=8.8,C3-H), 7.73(d,1H,J=2.8,C7-H),7.34(dd,1H,J=8.9,J=2.8,C9-H), 6.81(d,1H,J=8.8,C4-H),3.42(qu*,2H,--NH--CH₂ --CH₂ --), 2.52(t,2H,--CH₂ --CH₂ --NEt₂),2.48(qu,4H,--N(CH₂,CH₃)₂), 1.78(qt,2H,--CH₂ --CH₂ --CH₂ --),0.96(t,6H,--N(CH₂ --CH₃)₂).

Compound 1: R=OH, R₁ =CH₃, R₂ =H, n=2.

¹ H NMR (free base) (ME₂ SO-d₆) δ 10.00(s,1H,ex,C8-OH),9.02(t,1H,ex,--NH--CH₂ --), 8.11(d,1H,J=9.1,C10-H),7.83(d,1H,J=8.8,C3-H), 7.79(d,1H,J=2.9,C7-H),7.33(dd,1H,J=9.1,J=2.9,C9-H), 6.72(d,1H,J=8.8,C4-H),3.38(qu*,2H,--NH--CH₂ --CH₂ --), 3.02(s,3H,Cl--CH₃), 2.72(t,2H,--CH₂--CH₂ --NEt₂), 2.56(qu,4H,--N(CH₂ --CH₃)₂), 1.02(t,6H,--N(CH₂ --CH₃)₂).

Compound I: R=OH, R₁ =CH₂ CH₃, R₂ =CH₃, n=3.

¹ H NMR (free base) (Me₂ SO-d₆) δ 10.0(br s,1H,ex,C8-OH),8.91(t,1H,ex,--NH--CH₂ --), 8.08(d,1H,J=9.1,C10-H),7.80(d,1H,J=8.8,C3-H), 7.77(d,1H,J=3.0,C7-H),7.32(dd,1H,J=9.1,J=3.0,C9-H), 6.70(d,1H,J=8.8,C4-H),3.38(qu*,2H,--NH--CH₂ --CH₂ --), 3.00(s,3H,Cl--CH₃), 2.48(m,6H,--CH₂--CH₂ --N(CH₂ --CH₃)₂), 1.76(qt,2H,--CH₂ --CH₂ --CH₂ --).

Intermediates

Melting points, yields and molecular formulae of intermediates are setforth in Table I with reference to Scheme 1.

                  TABLE I                                                         ______________________________________                                        1-Substituted 4-Nitro-9(10H)-acridinones (b) and                              1-Substituted 4-Amino-7-methoxy-9-(10H)-acridinones (c)                                                         yield,                                                                              molecular                             Compd n     R       R.sub.1                                                                              mp, °C.                                                                       %     formula.sup.a                         ______________________________________                                        (b)   2     OCH.sub.3                                                                             CH.sub.3                                                                             242-243.sup.b                                                                        96    C.sub.18 H.sub.20 N.sub.4                                                     O.sub.4                               (b)   2     OCH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    178-179.sup.c                                                                        92    C.sub.20 H.sub.24 N.sub.4                                                     O.sub.4                               (b)   3     OCH.sub.3                                                                             CH.sub.3                                                                             165-166                                                                              94    C.sub.19 H.sub.22 N.sub.4                                                     O.sub.4                               (b)   3     OCH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    153-154.sup.d                                                                        97    C.sub.21 H.sub.26 N.sub.4                                                     O.sub.4                               (b)   2     OH      CH.sub.3                                                                             258-260                                                                              90    C.sub.17 H.sub.18 N.sub.4                                                     O.sub.4                               (b)   2     OH      CH.sub.2 CH.sub.3                                                                    227-229                                                                              94    C.sub.19 H.sub.22 N.sub.4                                                     O.sub.4                               (b)   3     OH      CH.sub.3                                                                             214-214.sup.e                                                                        82    C.sub.18 H.sub.20 N.sub.4                                                     O.sub.4                               (b)   3     OH      CH.sub.2 CH.sub.3                                                                    208-210                                                                              86    C.sub.20 H.sub.24 N.sub.4                                                     O.sub.4                               (c)   2     OCH.sub.3                                                                             CH.sub.3                                                                             240-243                                                                              79    C.sub.18 H.sub.22 N.sub.4                                                     O.sub.2,                                                         dec          2HCl                                  (c)   2     OCH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    227-231                                                                              74    C.sub.20 H.sub.26 N.sub.4                                                     O.sub.2,                                                         dec          2HCl                                  (c)   3     OCH.sub.3                                                                             CH.sub.3                                                                             232-235                                                                              80    C.sub.19 H.sub.24 N.sub.4                                                     O.sub.2,                                                         dec          2HCl                                  (c)   3     OCH.sub.3                                                                             CH.sub.2 CH.sub.3                                                                    180-185                                                                              84    C.sub.21 H.sub.28 N.sub.4                                                     O.sub.2,                                                         dec          3HCl                                  ______________________________________                                         .sup.a The analyses are within ±0.4% of the theoretical values for C,      and N. [lif.sup.b mp 234-237° C.; .sup.c mp 179-180° C.;        .sup.d mp 151-152° C.; .sup.e mp 212-213° C.; (Capps, D. B.     European Patent Appl. EP 145226, 1985; Chem. Abstr. 1985, 103, 215182s)].

Biological Tests In Vitro Cytoxicity Evaluation

The mouse L1210 leukemia cells (RPM1, USA) are grown in RPM1 1640 mediumsupplemented with 5% fetal calf serum and penicillin (1,000,000 unitslitre) plus streptomycin (100 mg/litre) in controlled air-5% CO₂humidified atmosphere at 37° C. L1210 mouse leukemia cells are seeded ata density of 5.10⁴ cells/ml. The tested compounds after being dissolvedin 50% ethanol are added, at four different concentrations, to the cellsuspensions. The cytotoxic activity (IC₅₀ value) of the tested compoundsis defined as their concentrations causing 50% growth inhibition after48 h, measured by cells protein contents and is determined fromdose-response curves by the method of: Konopa, J.; Matuszkiewicz, A.;Hrabowska, M.; Onoszko, K. Arzneim.-Forsch. 1974, 24, 1971.

In Vivo Antileukemic Evaluation

BDF₁ mice are injected ip with 10⁶ P388 lymphotic leukemia cells on dayO and treated ip on days 1-5 in accordance with the protocols describedby the National Cancer Institute: Geran, R. I.; Greenberg, R. H.;MacDonald, M. M.; Schumacher, A. M.; Abbot, B. J. Cancer Chemother, Re.,Part 3, 1972,3,1. The mean survival time (MST) for each treatment group(eight mice) is calculated and the percent of T/C was determined byusing the following formula: % T/C=(MST treated)/(MST control) 100.

Results of the Cytotoxicity Evaluation and Antileukemic Evaluation areset forth in Table II:

                                      TABLE II                                    __________________________________________________________________________    Formulae, melting paint, yields and activities against Murine L1210           in Vitro and P388 Leukemia in Vivo of Substituted 5-Aminoimidazo[4,5,1-de]    acridin-6-ones of formula I                                                    ##STR6##                                                                                                                           P388 leukemia in                                                  in vitro    vivo opt dose           Exam-                    yield            IC.sub.50   (mg/kg/                 ple n R   R.sub.1                                                                            R.sub.2                                                                          mp, °C..sup.a                                                                 %  formula.sup.b (μg/ml)                                                                            (μM)                                                                           per                                                                                %                  __________________________________________________________________________                                                               TC.sup.c           1   2 OCH.sub.3                                                                         CH.sub.2 CH.sub.3                                                                  H  250-254 dec.sup.d                                                                    68 C.sub.21 H.sub.24 N.sub.4 O.sub.2                                                           0.78 (±0.02)                                                                       1.8 100  183,                                                                          209                2   2 OCH.sub.3                                                                         CH.sub.3                                                                           H  254-258 dec                                                                          90 C.sub.19 H.sub.20 N.sub.4 O.sub.2 1.5HCl                                      0.75H.sub.2 O 0.65 (±0.07)                                                                       1.6 100  177,                                                                          136                3   2 OCH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                         255-259 dec                                                                          82 C.sub.20 H.sub.22 N.sub.4 O.sub.2 2                                           HCl.H.sub.2 O 0.34 (±0.09)                                                                       0.77                                                                              150  127                4   2 OCH.sub.3                                                                         CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                         238-241 dec.sup.e                                                                    70 C.sub.22 H.sub.28 N.sub.4 O.sub.2.2                                                         0.70 (±0.40)                                                                       1.55                                                                              150  136,                                                                          120                5   3 OCH.sub.3                                                                         CH.sub.3                                                                           H  237-241 dec                                                                          70 C.sub.20 H.sub.22 N.sub.4 O.sub.2.2                                           HCl.0.2H.sub.2 O                                                                            3.50 (±0.75)                                                                       8.25                                                                              150  164                6   3 OCH.sub.3                                                                         CH.sub.3                                                                           CH.sub.3                                                                         252-256 dec.sup.f                                                                    68 C.sub.21 H.sub.24 N.sub.4 O.sub.2.1.85                                                      1.40 (±0.60)                                                                       3.2 150  136                7   3 OCH.sub.3                                                                         CH.sub.2 CH.sub.3                                                                  H  246-250 dec                                                                          72 C.sub.22 H.sub.26 N.sub.4 O.sub.2.1.5                                                       1.10 (±0.32)                                                                       2.5 150  142                8   3 OCH.sub.3                                                                         CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                         203-208 dec                                                                          64 C.sub.23 H.sub.28 N.sub.4 O.sub.2.2                                           HCl.H.sub.2 O 0.70 (±0.17)                                                                       1.4 150  108                9   2 OH  CH.sub.3                                                                           H  260-264 dec                                                                          77 C.sub.18 H.sub.18 N.sub.4 O.sub.2.2                                           HCl.H.sub.2 O 0.02 (±0.01)                                                                       0.048                                                                             12.5 210,                                                                          210                10  2 OH  CH.sub.3                                                                           CH.sub.3                                                                         268-273 dec                                                                          68 C.sub.19 H.sub.20 N.sub.4 O.sub.2.2                                           HCl.2H.sub.2 O                                                                              0.06 (±0.03)                                                                       0.135                                                                             12.5 200,                                                                          250                11  2 OH  CH.sub.2 CH.sub.3                                                                  H  250-255 dec.sup.g                                                                    72 C.sub.20 H.sub.22 N.sub.4 O.sub.2.2                                           HCl.H.sub.2 O 0.013 (±0.008)                                                                     0.031                                                                             5    211,                                                                          175                12  2 OH  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                         260-265 dec.sup.h                                                                    78 C.sub.21 H.sub.24 N.sub.4 O.sub.2.1.5HCl                                      0.5H.sub.2 O  0.11 (±0.08)                                                                       0.25                                                                              75   280,                                                                          290                13  3 OH  CH.sub.3                                                                           H  247-251 dec                                                                          70 C.sub.19 H.sub.20 N.sub.4 O.sub.2.2                                                         0.014 (±0.005)                                                                     0.034                                                                             5    183                14  3 OH  CH.sub.3                                                                           CH.sub.3                                                                         268-271 dec.sup.i                                                                    69 C.sub.20 H.sub.22 N.sub.4 O.sub.2.2                                           HCl.0.5H.sub.2 O                                                                            0.10 (±0.07)                                                                       0.23                                                                              100  255                15  3 OH  CH.sub.2 CH.sub.3                                                                  H  269-272 dec.sup.j                                                                    70 C.sub.21 H.sub.21 N.sub.4 O.sub.2.2                                           HCl.H.sub.2 O 0.08 (±0.05)                                                                       0.18                                                                              25   309,                                                                          230                16  3 OH  CH.sub.2 CH.sub.3                                                                  CH.sub.3                                                                         238-242 dec.sup.k                                                                    66 C.sub.22 H.sub.26 N.sub.4 O.sub.2.2                                           HCl.H.sub.2 O 0.40 (±0.21)                                                                       0.89                                                                              25   150,                                                                          155                __________________________________________________________________________     *All the hydrochlorides were recrystallized from MeOHacetone and free         bases from benzenehexane.                                                     .sup.b Microanalyses are within ±0.4% of the theoretical values for C,     H and N.                                                                      .sup.c When two values are given, the second one represents the result        obtained during repeated independent multidose assay.                         .sup.d Free base mp 191-193° C.                                        .sup.e Free base mp 156-158° C.                                        .sup.f Free base mp 156-158° C.                                        .sup.g Free base mp 239-242° C.                                        .sup.h Free base mp 255-258° C.                                        .sup.i Free base mp 242-245° C.                                        .sup.j Free base mp 222-225° C.                                        .sup.k Free base mp 240-245° C.                                   

We claim:
 1. Compounds of formula I: ##STR7## in which: R represents:--OH or --OR', wherein R' represents C₁ -C₆ alkyl,R₁ ^(a) and R₁ ^(b),which may be identical or different, represent hydrogen or C₁ -C₆ alkyl,unsubstituted or substituted by a hydroxyl, an amino, a N'-alkylamino ora N',N'-dialkylamino group, such N'-alkyl group containing 1-4 carbonatoms, n is 2-5 and R₂ represents hydrogen, or straight chain C₁ -C₄alkyl, in the form of a free base or a pharmaceutically acceptable acidaddition salt thereof.
 2. Compounds according to claim 1, in which R₁^(a) and R₁ ^(b) are identical.
 3. Compounds according to claim 1, inwhich R₁ ^(a) and R₁ ^(b) or both represent a said substituted orunsubstituted C₁ -C₃ alkyl group.
 4. Compounds according to claim 1, inwhich n is 2 or
 3. 5. Compounds according to claim 1, in which R=--OH,R₁ ^(a) =R₁ ^(b) =methyl or ethyl, R₂ =hydrogen or methyl and n is 2 or3.
 6. The compound according to claim 1 wherein:R=--OH; R₁ ^(a) =R₁ ^(b)=--CH₃ ; R₂ =H; and n=2.
 7. The compound according to claim 1wherein:R=--OH; R₁ ^(a) =R₁ ^(b) =--CH₃ ; R₂ =CH₃ ; and n=2.
 8. Thecompound according to claim 1 wherein:R=--OCH₃ ; R₁ ^(a) =R₁ ^(b) =--CH₃; R₂ =H; and n=2.
 9. The compound according to claim 1 wherein:R=--OH;R₁ ^(a) =R₁ ^(b) =--CH₂ CH₃ ; R₂ =H; and n=2.
 10. The compound accordingto claim 1 wherein:R=--OH; R₁ ^(a) =R₁ ^(b) =--CH₂ CH₃ ; R₂ =CH₃ ; andn=2.
 11. The compound according to claim 1 wherein:R=--OCH₃ ; R₁ ^(a)=R₁ ^(b) =--CH₂ CH₃ ; R₂ =H; and n=2.
 12. The compound according toclaim 1 wherein:R=--OH; R₁ ^(a) =R₁ ^(b) =--CH₃ ; R₂ =CH₃ ; and n=2. 13.The compound according to claim 1 wherein:R=--OH; R₁ ^(a) =R₁ ^(b)=--CH₂ CH₃ ; R₂ =H; and n=2.
 14. A method for prophylaxis of leukemiawhich comprises administering to a patient an effective amount of anantineoplastic compound of formula (I) according to claim 1.